1. Field of the Invention
The present invention relates to a method for treating a motor neuron disease. More particularly, the present invention relates to a method for treating a motor neuron disease, comprising the step of administering a therapeutically effective amount of a compound having serotonin receptor antagonist activity or its pharmacologically acceptable salt or their solvate optionally together with a pharmaceutically acceptable carrier to a mammal for which the treatment of said disease is indicated.
2. Background Technology
Amyotrophic lateral sclerosis (ALS) is a lethal progressive disease caused by selective degeneration and falling-off of motor neuron cells. The amyotrophic lateral sclerosis is mainly developed in adults in their 40s to 50s. In many cases, muscle weakening and amyotrophy in arm's periphery take place at the onset of ALS, the legs are then affected, and, two to six years after the manifestation of symptoms of bulbar paralysis, the patient dies. On the other hand, the patient's eye movement and sensory system and intellectual functions are maintained without any abnormality.
It is said that about 90% of ALS is accounted for by sporadic ALS that is not genetic in origin while the remainder is familial ALS that is genetic in origin. A 30 to 95% decrease in astroglial glutamate transporter EAAT2 (GLT-1) function is observed in 60 to 70% of the patients suffering from sporadic ALS. Further, abnormality is observed in RNA editing of EAAT2 in the ALS affected area (Lin et al. Neuron 20, 589-602 (1998); and Meyer et al. J. Neurol Sci 170, 45-50 (1999)). Mutation of superoxide dismutase 1 (SOD1), which detoxifies active oxygen, is observed in about 20% of the patients suffering from familial ALS (Deng et al. Science 261, 1047-51 (1993); and Rosen et al. Nature 362, 59-62 (1993)). Rats and mice transgenic for mutated SOD1 gene develop ALS-like symptoms (Nagai et al. J Neurosci 21, 9246-9254 (2001); and Gurney et al. Science 264, 1772-1775 (1994)) and thus have been widely used as ALS models. The pathogenic mechanism of ALS has not been fully elucidated yet (Rowland and Schneider, N Engl J Med 344, 1688-1700 (2001); and Julien, Cell 104, 581-591 (2001)). However, for example, glutamate excitotoxicity (Kawahara et al. Nature 427, 801 (2004); and Lipton, Nat Med 10, 347 (2004)) and oxidative stress (Rosen et al. Nature 362, 59-62 (1993); Cleveland and Rothstein, Nat Rev Neurosci 2, 806-819 (2001); Julien, Cell 104, 581-591 (2001); and Fryer et al. J Neurochem 72, 500-513 (1999)) have been considered as participating in the pathogenic mechanism.
Search for therapeutic agents has been conducted based on these hypothetical mechanisms. At the present time, however, any satisfactory therapeutic agent was not found by the search. Riluzole is the only approved therapeutic agent for ALS which is said to have glutamate release inhibitory activity. The therapeutic effect of Riluzole, however, is so small that Riluzole is unsatisfactory as a therapeutic agent (Bensimon, N Engl J Med 330, 585-591 (1994); and Lacomblez, Lancet 347, 1425-1431 (1996)). For Radicut considered as scavenging free radicals and protecting nerve cells, placebo control double blind tests have been conducted and proceeded to phase II. Various neurotrophic factors such as ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) inhibit cell death of motor neuron cells in in-vitro and in-vivo tests (Arakawa et al. J Neurosci 10, 3507-3515 (1990); Henderson et al. Curr Opin Neurobiol 2, 770-775 (1993); Ishii and Marsh, Exp Neurol 124, 96-99 (1993); Lewis et al. Exp Neurol 124, 73-88 (1993); Sendtner et al. J Neurol Sci 124 Suppl, 77-83 (1994); and Lindsay, Ciba Found Symp 196, 39-48, discussion 48-53 (1996)) and thus are expected as therapeutic agents for ALS, and clinical development of therapeutic agents has been conducted but failed to confirm survival advantage (Storkebaum et al. Nat Neurosci 8, 85-92 (2005); and Thoenen and Sendtner, Nat Neurosci 5 Suppl, 1046-1050 (2002)).
It is known that, as with a glutamate nervous system, a serotonin (5HT) nervous system applies excitatory stimuli to spinal motor neuron cells and is involved in the mechanism of the generation of plateau potential necessary for rhythmical motion, such as locomotion, and fictive locomotion (Hultborn and Kiehn, Curr Opin Neurobiol 2, 770-775 (1992); and Perrier and Hounsgaard, J Neurophysiol 89, 954-959 (2003)). For motor neuron cells, many data on the expression of four 5HT receptors, i.e., 5HT1A, 5HT1B, 5HT2A, and 5HT2C receptors, have been reported (Volgin et al. Eur J Neurosci 17, 1179-1188 (2003); and Ridet et al. J Neurosci Res 38, 109-121 (1994)). 5HT1A receptors excite motor neuron cells in the fetal phase (Hayashi et al. Brain Res Dev Brain Res 102, 21-33 (1997); and Wang and Dun, J Physiol 430, 87-103 (1990)), but on the other hand, after birth, the expression level of 5HT1A decreases (Talley et al. J Neurosci 17, 4473-4485 (1997)). It is known that the expression level of 5HT2A receptor increases with the growth thereof and, in mature motor neuron cells, the 5HT2A receptor is the main receptor for 5HT (Volgin et al. Eur J Neurosci 17, 1179-1188 (2003)). In particular, the 5HT2A receptor is known to regulate the rhythmical motion (M. Antri et al. Eur J Neurosci 16, 467-476 (2002)). There is a report that, in human autopsy samples, 5HT is present in a high concentration of 2 to 3 μM in a spinal ventral tissue, and, further, a tendency toward a further increase in the concentration of 5HT in autopsy samples of ALS patients has also been reported (Bertel et al. Brain Res 566, 54-60 (1991)). These reports demonstrate physiological importance of 5HT in motor function and suggest the participation of 5HT in selective falling-off of motor neuron cells in ALS.
There is a report that 5-hydroxytryptophan (5HTP), which is a 5HT precursor, prolongs the life of ALS model mice (Turner et al., Amyotroph Lateral Scler Other Motor Neuron Disord 4, 171-176 (2003)). In this report, however, 5HTP is peripherally administered and whether or not the concentration of 5HT in the brain is increased is not examined. Further, there is no description on the behavior of 5HT induction typified by head twitch. Accordingly, it has been regarded that there is a doubt about whether or not the prolongation of the life is derived from 5HT.
Clinical trials on the effect of some compounds having neuroprotective activity on ALS have been carried out. For example, SR57746A (Xaliproden) also acts agonistically on 5HT1A receptors and, in studies using cultured motor neuron cells, has been found to have neuroprotective activity (Iwasaki et al. J Neurol Sci 160 Suppl 1, S92-96 (1998); and Labie et al. Br J Pharmacol 127, 139-144 (1999)). A double blind placebo test has also been carried out (Meininger et al. Amyotroph Lateral Scler Other Motor Neuron Disord 5, 107-117 (2004); and Lacomblez et al. Amyotroph Lateral Scler Other Motor Neuron Disord 5, 99-106 (2004)). As a result, any clinically significant difference could not have been observed for life prolongation and delay of a deterioration in motor function although some tendency toward the development of this effect was confirmed. Buspirone, which has been found to have neuroprotective activity and is under clinical trials, is also a 5HT1A receptor agonist and is known as an antianxiety agent (Jann M W. Pharmacotherapy. 8(2), 100-116(1988)). These 5HT1A receptor agonists, however, have been studied aiming at clinical use through the utilization of the neuroprotective action, and the action thereof as 5HT1A receptor agonists has not been expected.
Clozapine, which is a third-generation therapeutic agent for schizophrenia, has also been found to have neuroprotective activity and has been reported to delay disordered walk function and death of ALS model mices (Turner et al. J Neurosci Res. 74, 605-613 (2003)). Clozapine is a compound which is selectively bound to 5HT2A receptors rather than D2 receptors (Naheed and Green, Neurosci Lett 79, 351-354 (2001)). In studies conducted by Turner et al., however, any observation of 5HT2A receptor has not been conducted, and the suppression of progress of ALS by taking advantage of 5HT2A receptor antagonist activity has not been expected. Further, administration at high dose has shortened survival time by contrast.